the most common and unrecognized comorbidity

1. Iron deficiency in Heart failure:
Most Common,
Unrecognised
&
Undertreated Comorbidity
Dr. Nagula Praveen, MD, DM
Assistant Professor of Cardiology
Osmania General Hospital, Hyderabad
drpraveennagula@gmail.com
@kizashipraveen

2. The burden of Heart Failure is increasing
at an alarming rate in India.
Prevalence of HF ranges from 13 to 46 lakhs, with an
annual incidence of 5 -18 lakhs1.
*Parameters India US & Europe
Age 53 yrs 65 - 75
EF 29.2% 34.4-39%
Death 30.8% 4-7%
Re-hospitalization 39.5% 24 -31%
Death post discharge 26.3% 5-15%
‘23% Heart failure
patients die within a
year of diagnosis’
INTER-CHF study
Patients with Heart Failure in India
 Affected at a Younger Age
 High Morbidity and Mortality and worsens the patient’s quality
of life - in hospital and after discharge
S. Mishra et al. Indian Heart Journal 70 (2018) 105–127

3. IRON METABOLISM

5. Depletion of iron available in the circulation (bound to transferrin) and iron stores (ferritin in the liver and iron in the RES)
Depletion of iron available in the circulation (bound to transferrin) but not iron stores
Types of Iron Deficiency
Reduced iron storage
Reduced iron mobilization

6. 6

7. Role of Hepcidin
Hepcidin is a hormone produced by
the liver.
Hepcidin functions to regulate (inhibit)
iron transport across the gut mucosa
macrophages
In states of high hepcidin levels
(including inflammatory states like in
chronic disease), serum iron levels
can drop because iron is trapped
inside macrophages
Plasma
Fe-Tf
Spleen
Bone
marrow
RBC
Liver
Duodenum
Inflammation
Nemeth E, et al. Blood. 2003;101:2461-2463.
Nemeth E, et al. J Clin Invest. 2004;113:1271-1276.
Courtesy of Tomas Ganz, PhD, MD, and Elizabeta Nemeth, MD.

9. Ten Principles for Successful Treatment of Heart Failure

10. HF – Non Cardiac Comorbidities

11. 11

12. Dealing with comorbidities in heart failure
Iron deficiency is an important comorbidity and is
prevalent in patients with heart failure ;
however, it is often neglected.
Iron deficiency:
A comorbidity that goes
unnoticed in heart failure

13. Iron Deficiency is common in patients with HF
8-10 Mn Individuals
are affected by Heart
Failure in India 1
1 - Chaturvedi et al Heart failure in India. The Indus Study
6-8 Mn Iron Deficiency
in CHF patients in India 2
3 out of 4
Heart failure
patients have
ID in India
Country wise ID prevalence in HF
USA
61.3%
Europe
37-50 %
Singapore
61.4 %
Singapore Indian
82 %
S.K. Sharma et.al. Indian Heart J. 2016 Jul-Aug; 68(4): 493–497.
Alarming burden of ID with HF in India
Up to 50% of patient with HF have concomitant Iron Deficiency

15. Iron Deficiency is associated with increased
Mortality in Acute HF
Survival amongst 165 acute HF Patients by iron status
sTfR - serum soluble transferrin receptor European Heart Journal (2014) 35, 2468–2476
Both low hepcidin and high sTfR predicted higher 12-month mortality rates in patients with AHF.

16. Transferrin

17. Iron Deficiency
a Common Neglected Burden in Heart Failure
What do the guidelines say?

18. 2016 ESC guidelines for the diagnosis and treatment of HF -
In these guidelines
Iron Deficiency is defined as follows:
Serum ferritin <100 µg/L
(absolute iron deficiency),
or
Serum ferritin 100–299 µg/L and
“transferrin saturation” TSAT <20%
(functional iron deficiency).

19. All patients with HF are recommended to be screened for
iron deficiency based on serum ferritin and TSAT

20. Guidelines recommendation for IV FCM
Ponikowski P, (…), Jankowska EA et al. Eur Heart J 2016;37:2129–200.

21. Adapted from: Beard JL. J Nutr 2001;131:568S–79S.
Challenges in the Diagnosis of Iron Deficiency
Despite ESC Guidelines
- Stating that Iron Deficiency is a common comorbidity in patients with
Heart Failure
- Recommending regular screening and assessment
Lack of Awareness of Iron
Deficiency by clinicians

22. Iron Deficiency and Anemia are distinct
Comorbidities of HF

23. Challenges in the Diagnosis of Iron Deficiency
HF & ID - Similar symptoms for different problem!!

24. Iron deficiency & Anemia…what
to check?

25. Parameters for the assessment of Iron Status
MCV - mean corpuscular volume
Zinc Protoporphyrin(ZPP) - ZPP is used as a screening marker of iron deficiency in individual pregnant women and children, but also to
assess population iron status in combination with haemoglobin concentration.
sTfR - serum soluble transferrin receptor
Hb MCV Ferritin TSAT ZPP sTFR
ID N N N N N
ID Erythropoiesis N N
IDA N or
FID N or N or
ACD N or N or N or N or
ACD + ID N or N or (or N?)

26. Blood Tests to be used to diagnose ID

27. Algorithm for the screening and diagnosis of ID in HF

28. ID is common in Patients with HF regardless of the presence
of Anemia

29. ID with or without Anemia
Peak oxygen consumption
(–) anaemia
(–) ID
(+) anaemia
(–) ID
(–) anaemia
(+) ID
(+) anaemia
(+) ID
Iron deficiencyp<0.001
Anaemia p=0.15
Interactions p=0.94
17
16
15
PeakVO2(mL/min/kg)
14
13
12
Klip IT et al. Am Heart J 2013;165:575–82.
ID defined as: serum ferritin <100 μg/L, or serum ferritin 100–299 μg/L with TSAT <20%.
Anaemia defined as: haemoglobin level <12 g/dL in women and <13 g/dL in men.
No ID
No anaemia
No ID
Anaemia
ID
No anaemia
ID
Anaemia
HR(95%CI)forall-causemortality

30. Myocardial iron content is reduced in advanced heart failure
300
250
200
150
100
50
p<0.001
MyocardialIron
[µg/gdryweight]
Myocardial Iron content
A comparison of the myocardial iron content in explanted hearts of patients
with advanced HF versus normal donor hearts as control
Iron content was significantly reduced in
advanced HF compared with the controls
 This may worsen mitochondrial function
• Melenovsky V et al. Eur J Heart Fail 2017;19:522–30

31. IRON MATTERS FOR CONTRACTILITY
Contractility is impaired in iron deficient cardiomyocytes and can be improved
with iron
Iron deficiency reduced contractile force by 43% (P<0.05)
Subsequent addition of transferrin-bound iron could reverse this effect
Myocardial contractility
Adapted from Hoes et al. 2018
100
6
99
98
97
96
95
543210
Time (s)
Fractionareal(%)
Control
4 days iron deficient
4 days Iron deficient + transferrin-bound iron
Control cardiomyocytes
Iron deficient cardiomyocytes
In vitro model using human embryonic stem cell-derived cardiomyocytes made
profoundly iron deficient by the administration of the iron chelator deferoxamine (DFO) • Hoes MF et al. Eur J Heart Fail. 2018;20:910-919

32. Iron deficiency in heart failure
Clinical question
• Is intravenous iron more effective than oral iron for the treatment of
iron deficiency in patients with heart failure ?
Iron therapy for the treatment of iron deficiency in chronic heart
failure: intravenous or oral ?

33. • In FAIR-HF, 459 iron deficient CHF patients
were randomized to i.v. ferric carboxymaltose or
saline and assessed at 4, 12, and 24 weeks.
• At 4 weeks, FCM was associated with greater
reductions in weight (0.02) and PVS (P <
0.0001), and a trend for improved peripheral
oedema at 24 weeks (0.07).
• Irrespective of treatment allocation, patients with
a decrease in PVS from baseline to week 24
had higher increments in 6 min walking distance
(61.4 m vs. 43.5 m, 0.02) and were more likely
to improve their NYHA class (33.3% vs. 15.5%,
0.001).
ESC Heart Fail 2019 Aug; 6(4): 621–628
Change in markers of congestion in FAIR-HF
Alterations from baseline to week 24
Effect of ferric carboxymaltose on calculated plasma
volume status and clinical congestion: a FAIR-HF substudy

34. A PVS > - 4% at baseline predicted worse outcomes even
after adjustment for treatment assignment (hazard ratio
1.88, 95% confidence interval 1.01–3.51, 0.046).
Baseline PVS categories (≤-4% vs. >-4%)
and survival
• IV iron therapy with FCM is associated with
reductions in PVS and weight even as early
as 4 weeks after treatment initiation.
• This supports a potential decongestive
effect of IV iron therapy in CHF that might be
one mechanism via which iron repletion
improves symptoms, quality of life, and
exercise performance in this population.
• Calculated PVS, a simple novel marker of
fluid overload, predicted deaths and
hospitalizations in the FAIR-HF cohort
irrespective of treatment assignment.
ESC Heart Fail 2019 Aug; 6(4): 621–628
Effect of ferric carboxymaltose on calculated plasma
volume status and clinical congestion: a FAIR-HF substudy

35. • Poorly tolerated
• GI absorption impaired , standard doses often insufficient
• Drug interactions
• Hepcidin issues
- Increased hepcidin levels, typical in inflammatory states such as HF ,
precludes resorption of iron from the gut
- High levels of hepcidin can “TRAP” iron in storage cells
Iron therapy for the treatment of iron deficiency
in chronic heart failure: intravenous or oral?
Oral therapy is not so effective

36. Effect of oral or i.v. iron therapy on ‘hepcidin block’ of iron release
from macrophages.
(A) Under normal circumstances,
∼25 mg of stored iron per day is
transported out of macrophages to
plasma transferrin by the iron transporter
protein ferroportin.
(B) In chronic disease, elevated levels of
hepcidin cause degradation of
ferroportin, restricting ferroportinmediated
transport to ∼15 mg iron/day

37. Effect of oral or i.v. iron therapy on ‘hepcidin block’ of iron release
from macrophages.
(C) Oral iron The rate of iron
absorption from iron therapy is
inadequate to influence this ‘hepcidin
block’.
(D) I.V. iron therapy results in high
intracellular iron levels which overcome
the ‘hepcidin block’ by stimulating
overexpression of ferroportin

38. Oral iron of no benefit in HF with ID
Conclusions and Relevance Among participants with HFrEF with iron
deficiency, high-dose oral iron did not improve exercise capacity over 16 weeks.
These results do not support use of oral iron supplementation in patients
with HFrEF.

40. 1. CosmoFer Summary of Product Characteristics. Vitaline Pharma UK. Last updated August 2007
2. Ferrlecit Summary of Product Characteristics. Rhone-Poulenc-Rorer, Dagenham, UK. Last updated July 1996
3. Venofer Summary of Product Characteristics. Syner-Med (Pharmaceutical Products) Ltd, UK. Last updated August 2006
4. Feraheme Summary of Product Characteristics. AMAG Pharmaceuticals, Inc, Lexington, MA, USA. June 2009
5. Ferinject Summary of Product Characteristics. Syner-Med (Pharmaceutical Products) Ltd. Last updated July 2007
Maximum single
dose(mg iron)
Administration
time by drip
infusion for
maximum
single dose**
Test dose
required?
20mg/kg
Yes
62.5mg
Max 125mg
-
4-6 hours
30 min
for 62.5 mg
200mg*
4mg/kg
Yes/No***
30 min
1000mg
or 15mg/kg
-
15 min
(Infusion and
injection)
Iron dextran Iron
gluconate
Iron
sucrose
Ferric
carboxymaltose
* Maximum dose of 500mg iron can be administered in some countries
** Except for Feraheme®
***Depending on the country
510mg
-
Ferumoxytol
17 seconds
(i.v. injection
only)
Ferric Carboxymaltose has added advantage over the other IV formulation.
Evidence-Based Answer - Ferric Carboxymaltose is preferred agent
(other preparations not as well studied)
IV iron is the only valid treatment option for ID in HF

41. Clinical Evidences of IV Ferric Carboxymaltose Therapy in HF
FER-CARS-01 META-ANALYSIS
Arutyunov et al.
2009– HFA
Congress, Nice,
France
Anker S. et al.
2009 – NEJM)
Ponikowski P.
et al. 2014 -
European
Heart Journal
Anker S. et al.
2015 - ESC
Congress,
Seville, Spain
Van Veldhuisen
DJ et al. 2016-
AHA Congress,
New Orleans,
USA

42. FCM, ferric carboxymaltose
Meta-analysis on individual patient data with FCM:
Efficacy outcomes
Rate ratio analysis (recurrent event analyses)
Recurrent event outcomes
FCM
(N=504)
Placebo (N=335) Rate Ratio (95%CI) p
CV hospitalisation and CV death 69 (23.0) 92 (40.9) 0.59 (0.40-0.88) 0.009
HF hospitalisation and CV death 39 (13.0) 60 (26.7) 0.53 (0.33-0.86) 0.011
CV hospitalisation and all-cause death 71 (23.7) 94 (41.8) 0.60 (0.41-0.88) 0.009
HF hospitalisation and all-cause death 41 (13.7) 62 (27.6) 0.54 (0.34-0.87) 0.011
All-cause hospitalisation and
all-cause death
108 (36.1) 118 (52.5) 0.73 (0.52-1.01) 0.060
HF hospitalisation 22 (7.3) 43 (19.1) 0.41 (0.23-0.73) 0.003
CV hospitalisation 52 (17.4) 75 (33.3) 0.54 (0.36-0.83) 0.004
All-cause hospitalisation 89 (29.7) 99 (44.0) 0.71 (0.50-1.01) 0.056
Anker SD et al. Eur J Heart Failure 2017

43. • Ferric carboxymaltose
improves functional capacity,
symptoms, and quality of life
of HF patients with iron
deficiency.
• A meta-analysis of data from
the four major randomized
controlled trials conducted,
to date, demonstrated also a
reduction in recurrent CV
hospitalizations.
December 2019: ESC Heart Failure

44. Ongoing clinical trials addressing gaps in evidence
Morbidity and Mortality in HFrEF HFpEF AHF

45. Key Home message
Iron deficiency
 an important comorbidity and is prevalent in patients with heart failure however it is
often neglected.
 Observed in almost 76% of Heart Failure Indian patients.
 prevalent in chronic heart failure (also in non-anaemics)
 relates to a reduced exercise tolerance and impaired quality of Life
 associated with substantially higher Mortality Risk
 directly affects Cardiomyocytes function, Impairing mitochondria respiration and
reducing contractility
 Treatment with Ferric Carboxymaltose improves Morbidity & Mortality in patients with
HF and iron deficiency

46. Future Direction - Iron deficiency is an important
comorbidity and is prevalent also in patients with
HFpEF & AHF, however it is often neglected.